Abstract
Indian Journal of Modern Research and Reviews, 2026; 4(9): 157-167
QBD-Based Optimization of a Lipid–Polymer Hybrid Nanoparticle System for Sustained Drug Release
Author Name: Sachin Sharma, Anshu Patel, Neha Yadav
Abstract
<p>Lipid–polymer hybrid nanoparticles (LPHNs) are core–shell nanocarriers that merge the mechanical robustness and tunable drug release of biodegradable polymeric nanoparticles with the biomimetic, membrane-compatible surface of liposomes. Because the performance of such multicomponent colloidal systems depends on a large number of interacting material attributes and process parameters, empirical one-factor-at-a-time development is inefficient and often fails to guarantee reproducible quality. This article presents a Quality-by-Design (QBD) framework for the systematic development and optimization of a poly (lactic-co-glycolic acid) (PLGA)–lecithin–DSPE-PEG hybrid nanoparticle system intended for sustained release of a poorly water-soluble model drug. A Quality Target Product Profile (QTPP) was defined, from which critical quality attributes (CQAs) — particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE%), drug loading (DL%), and cumulative in vitro drug release — were identified. Risk assessment using an Ishikawa (fishbone) diagram and Failure Mode and Effects Analysis (FMEA) prioritised lipid: polymer ratio, polyvinyl alcohol (PVA) concentration, and sonication time as critical material/process attributes. These factors were screened using a Plackett–Burman design and subsequently optimized using a three-factor, three-level Box–Behnken design (17 runs) coupled with response-surface methodology (RSM). Second-order polynomial models were validated by analysis of variance (ANOVA), and a design space was constructed using overlay-contour and desirability-function analysis. The optimized formulation exhibited a mean particle size of 148.6 ± 4.2 nm, PDI of 0.176 ± 0.02, zeta potential of −28.4 ± 3.1 mV, entrapment efficiency of 84.7 ± 2.6%, and drug loading of 9.3 ± 0.4%. In vitro release in phosphate-buffered saline (pH 7.4, 37 °C) showed a biphasic profile with an initial burst of 18.4% within 2 h followed by sustained release reaching 91.2% over 72 h; the release data best fit the Korsmeyer–Peppas model (R² = 0.986, n = 0.46), indicating a diffusion-dominant, quasi-Fickian mechanism. Accelerated and long-term stability studies over three months confirmed acceptable colloidal and chemical stability under refrigerated storage. These results demonstrate that a structured QBD approach enables rational, risk-based, and statistically validated development of lipid–polymer hybrid nanocarriers with predictable sustained-release performance, supporting their translational and regulatory readiness.</p>
Keywords
Quality by Design; lipid–polymer hybrid nanoparticles; Box–Behnken design; response surface methodology; sustained drug release; PLGA; design space; risk assessment.
